Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXF5ICU)

• DOT Name: Gamma-aminobutyric acid receptor subunit epsilon (GABRE)
• Synonyms: GABA(A) receptor subunit epsilon
• Gene Name: GABRE
• UniProt ID: GBRE_HUMAN
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MLSKVLPVLLGILLILQSRVEGPQTESKNEASSRDVVYGPQPQPLENQLLSEETKSTETE
  TGSRVGKLPEASRILNTILSNYDHKLRPGIGEKPTVVTVEISVNSLGPLSILDMEYTIDI
  IFSQTWYDERLCYNDTFESLVLNGNVVSQLWIPDTFFRNSKRTHEHEITMPNQMVRIYKD
  GKVLYTIRMTIDAGCSLHMLRFPMDSHSCPLSFSSFSYPENEMIYKWENFKLEINEKNSW
  KLFQFDFTGVSNKTEIITTPVGDFMVMTIFFNVSRRFGYVAFQNYVPSSVTTMLSWVSFW
  IKTESAPARTSLGITSVLTMTTLGTFSRKNFPRVSYITALDFYIAICFVFCFCALLEFAV
  LNFLIYNQTKAHASPKLRHPRINSRAHARTRARSRACARQHQEAFVCQIVTTEGSDGEER
  PSCSAQQPPSPGSPEGPRSLCSKLACCEWCKRFKKYFCMVPDCEGSTWQQGRLCIHVYRL
  DNYSRVVFPVTFFFFNVLYWLVCLNL
• Function: GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
• Tissue Specificity: Expressed in many tissues. Highest levels of expression in adult heart and placenta.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Retrograde endocan.binoid sig.ling (hsa04723)
  GABAergic sy.pse (hsa04727)
  Morphine addiction (hsa05032)
  Nicotine addiction (hsa05033)

Molecular Interaction Atlas (MIA) of This DOT

11 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Gamma-aminobutyric acid receptor subunit epsilon (GABRE).	[1]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Gamma-aminobutyric acid receptor subunit epsilon (GABRE).	[2]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Gamma-aminobutyric acid receptor subunit epsilon (GABRE).	[3]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Gamma-aminobutyric acid receptor subunit epsilon (GABRE).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Gamma-aminobutyric acid receptor subunit epsilon (GABRE).	[5]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Gamma-aminobutyric acid receptor subunit epsilon (GABRE).	[6]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Gamma-aminobutyric acid receptor subunit epsilon (GABRE).	[7]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Gamma-aminobutyric acid receptor subunit epsilon (GABRE).	[8]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Gamma-aminobutyric acid receptor subunit epsilon (GABRE).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Gamma-aminobutyric acid receptor subunit epsilon (GABRE).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Gamma-aminobutyric acid receptor subunit epsilon (GABRE).	[13]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Gamma-aminobutyric acid receptor subunit epsilon (GABRE).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Gamma-aminobutyric acid receptor subunit epsilon (GABRE).	[12]

References

• [1] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [2] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [3] Gonadal steroids regulate GABAA receptor subunit mRNA expression in NT2-N neurons. Brain Res Mol Brain Res. 2005 Aug 18;138(2):105-15. doi: 10.1016/j.molbrainres.2004.10.047.
• [4] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [5] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [6] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [7] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [8] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [9] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [10] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [11] BET bromodomain protein inhibition is a therapeutic option for medulloblastoma. Oncotarget. 2013 Nov;4(11):2080-95.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.